Molecular Predictors of Response to Tyrosine Kinase Inhibitors in Lung Cancer.
Lung cancer continues to be the leading cause of cancer-related deaths in the United States and worldwide. While aggressive chemotherapy produces a positive response in approximately 30% of the patients, the 5–year survival rate has remained static, at about 14%, for the past 3 decades. Tyrosine kinase inhibitors (TKIs) are a new type of agent that targets a specific molecular defect in the lung cancer cell, namely overactivation of the EGFR pathway. This pathway leads to uncontrolled tumor growth. Although these agents may be ineffective in patients whose tumors do not have an activated EGFR pathway, they can be highly effective in selected groups of patients whose tumors do. We suggest that in order to establish the molecular status of the EGFR pathway and determine which tumor will be susceptible to anti-EGFR therapy, one must assess the activation level of EGFR and the activation level of Akt, Erk and Stat3, cytosolic end points to the three branches of the EGFR signaling pathway. In addition, one must assess the genetic status of the egfr, ras and pten gene, also members of the EGFR pathway which are often mutated or deleted in lung cancer cells. We are conducting these tests and correlating them with response to anti-EGFR therapy, to clearly determine their utility. Our goal is to be able to prospectively categorize patients in order to offer TKIs to patients who will derive benefit from this therapy and not delay alternative treatment to those patients who will not.
Molecular Predictors of Temozolomide Response in Gliomas.
Alkylating agents are among the most effective cytotoxic agents to treat malignant gliomas. Temozolomide, a second generation alkylating agent, is approved for the treatment of newly diagnosed glioblastoma multiforme and refractory anaplastic astrocytoma. Unfortunately, this agent yields an objective response or stable disease in only 50-60% of these patients. The goal of this study is to understand the molecular mechanisms responsible for temozolomide insensitivity/resistance in the reminder 40-50% of the patients. We hypothesize that insensitivity to temozolomide can be attributed to 3 possible mechanisms: 1) alterations in the DNA damage detection and repair pathways; 2) alterations in the control of cell cycle checkpoints; and 3) selection and growth of cells with “stem-like” phenotypes. This study proposes to analyze the status of key proteins that serve as sensors of the role that each of these mechanisms may be playing in producing temozolomide-insensitive tumors. Specifically, we plan to evaluate the expression of direct repair enzyme, MGMT and the activity of the Mismatch Repair pathway. We also plan to evaluate the expression level of p53, Akt, and stem cell markers, Nestin and CD133. The results of this study will allow a better understanding of the molecular factors that play a role in temozolomide insensitivity in our population and will lead us in the selection of the patients most likely to benefit from temozolomide therapy.
MGMT and MMR testing in NSCLC, a role in the selection of temozolomide responders
Non-small cell lung cancer patients suffer from one of the highest rate of morbidity and mortality and represent an important population for which to target efforts to increase the size of the chemotherapeutic arsenal. Temozolomide is not currently used in the treatment of NSCLC, but it is approved for the treatment of gliomas and is also used against melanomas. The molecular biology of the lung cancer cell suggests that temozolomide may be very effective in a specific subset of these tumors. The cell-killing effect of alkylating agents such as temozolomide is affected by the direct repair enzyme, MGMT, and by the mismatch repair system (MMR). The status of these repair processes can be assessed by MGMT promoter hypermethylation and by MSI testing of tumor samples. These tests may define an efficient protocol to select potential temozolomide beneficiaries among NSCLC.
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